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Gadolinium-based contrast agents (Gd-CAs), particularly the non-ionic linear chelates gadodiamide (Omniscan, GE Healthcare, USA) and gadoversetamide (OptiMark, Covidien, USA), were reported to cause an artificial decrease in serum calcium when colorimetric methods of calcium measurement were used [1, 2]. This interference was not observed with either ionic linear chelates or macrocyclic agents although, at high concentrations, the ionic linear chelate gadopentetate dimeglumine (Magnevist, Bayer Schering, Germany) may interfere with calcium determination when methylthymol blue is employed [3]. The potential interference of four Gd-CAs — Omniscan, OptiMark, Magnevist and the macrocyclic agent gadoteridol (ProHance, Bracco, Italy) — on multiple serum assays was reported in a comprehensive study [4]. The negative interference of non-ionic linear chelates on serum calcium was confirmed and a further negative interference with colorimetric measurements of serum zinc and angiotensin-converting enzyme was reported. Positive interference by these agents was detected for serum magnesium and total iron binding capacity assays, whereas both positive and negative interference was shown with iron assays. No interference with the measurement of serum creatinine was observed [4]. The report concluded that the non-ionic linear chelates Omniscan and OptiMark are more likely to produce a clinically significant interference than is Magnevist or ProHance [4].
We have recently obtained evidence for interference between Gd-CAs and assays for serum creatinine. Five Gd-CAs were examined: Omniscan, Magnevist, OptiMark, gadobutrol (Gadovist, Bayer Schering, Germany) and gadoterate meglumine (Dotarem, Guerbet, France). Omniscan contains 5% free ligand (caldiamide); a solution of gadodiamide without free ligand provided by Guerbet was also examined. Pooled human serum obtained from healthy volunteers in the Academic Nephrology Unit, University of Sheffield, was supplemented with the six contrast agents to final concentrations of 0.5 mmol l–1, 5 mmol l–1 and 50 mmol l–1. The Gd concentration for Gadovist was 1 mol l–1 but for all the other preparations was 0.5 mol l–1. The dilution of each contrast agent was performed in 0.9% saline. Serum without addition of contrast agents formed the control group. Samples were assayed for creatinine in quadruplicate by two different analytical techniques: the Jaffe kinetic reaction and an enzymatic assay. In the Jaffe kinetic reaction (Beckman, LX-20; Beckman Coulter, California, USA), creatinine reacts with picric acid under alkaline conditions to form a colour complex, detected at 510 nm. The rate of formation of colour is proportional to the creatinine concentration in the sample. The enzymatic assay (Vitros 950; Ortho-Clinical Diagnostics, Johnson & Johnson, High Wycombe, UK) involves four enzymatic steps. Creatinine is converted to creatine by creatinine amidohydolase; the creatine to sarcosine by creatine amidinohydrolase; and the sarcosine to hydrogen peroxide by sarcosine oxidase. The final colorimetric endpoint involves a reaction between hydrogen peroxide and a leuco dye requiring peroxidase.
No interference was observed using the enzymatic assay for any agent examined (Figure 1
). However, when the Jaffe kinetic reaction was employed, Omniscan (containing 5% free ligand), gadodiamide (no free ligand) and OptiMark, (containing 10% free ligand) all produced similar marked false positive measurements at 50 mmol l–1 (p<0.001 vs control analysis of variance (ANOVA)) (Figure 2). Interference was absent at 0.5 mmol l–1 and minimal at 5 mmol l–1. No interference was observed for Magnevist, Dotarem or Gadovist at any concentration examined.
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0.5–1 mmol l–1 is present in the serum immediately after the bolus administration of a standard dose of Gd-CA (0.1 mmol kg–1 body weight) [5]. Hence, interference with serum creatinine assayed by the Jaffe kinetic reaction may not be a major problem in clinical practice. However, in animal studies in vivo, the measurement of serum creatinine by the Jaffe kinetic reaction should be avoided with Omniscan and OptiMark when large doses of Gd-CAs (
2.5 mmol kg–1 body weight) are employed. Mechanisms suggested for such assay interference include dissociation of the Gd-CA complex, as false-positive measurements were only observed with agents of low stability. However, whether the free gadolinium, free ligand or the undissociated chelate was responsible is at present unclear.
1 Academic Department of Nephrology, University of Sheffield, 2 Diagnostic Imaging Department, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK, E-mail: sameh.morcos{at}sth.nhs.uk
Received for publication January 26, 2009. Accepted for publication January 27, 2009.
References
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